Polymorphic and Quantum Chemistry Characterization of Candesartan Cilexetil: Importance for the Correct Drug Classification According to Biopharmaceutics Classification System

Abstract

The recommended method for the biopharmaceutical evaluation of drug solubility is the shake flask; however, there are discrepancies reported about the solubility of certain compounds measured with this method, one of them is candesartan cilexetil. The present work aimed to elucidate the solubility of candesartan cilexetil by associating others assays such as stability determination, polymorphic characterization and in silico calculations of intrinsic solubility, ionized species, and electronic structures using quantum chemistry descriptors (frontier molecular orbitals and Fukui functions). For the complete biopharmaceutical classification, we also reviewed the permeability data available. The polymorphic form used was previously identified as the form I of candesartan cilexetil. The solubility was evaluated in biorelevant media in the pH range of 1.2-6.8 at 37.0°C according to the stability previously assessed. The solubility of candesartan cilexetil is pH dependent and the dose/solubility ratios obtained demonstrated the low solubility of the prodrug. The in silico calculations supported the found results and evidenced the main groups involved in the solvation, benzimidazole, and tetrazol-biphenyl. The human absolute bioavailability reported demonstrates that candesartan cilexetil has low permeability and when associated with the low solubility allows to classify it as class 4 of the Biopharmaceutics Classification System.

Impact of Solvent Selection and Absorptivity on Dissolution Testing of Acetylsalicylic Acid Enteric-Coated Tablets

“…As a result, dissolution media needs to be carefully selected to simulate in vivo dissolution based on physiological variations across the gastrointestinal tract (GIT) (8). In particular, pH of the dissolution medium is a crucial element that dictates the dissolution behavior, as it directly affects solubility and ionization of weakly acidic and basic drugs (9)(10)(11). The pH varies considerably across the GIT; the highly acidic stomach pH of 1.2 in the fasted state rises to pH 4.9 in the fed state (12).…”